Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
  • C07C69/616—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety polycyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/58—Preparation of carboxylic acid halides
  • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
  • C07C57/38—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings polycyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
  • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings

Definitions

• This invention relates to a method of treating inflammation, and more particularly, it relates to anti-inflammatory compositions having as their active constituent the compound 4-phenyl-a-methyl-phenylacetic acid, or salts, esters, anhydride or amide derivatives of this acid.
• a more particular object of this invention is to provide a method of treatment of arthritis utilizing a chemical compound which possesses a high degree of anti-inflammatory activity, and which gives rise to a minimum of adverse side eifects upon administration.
• the active compound of the invention has the formula:
• M is hydroXyl, alkoxy, alkenylkoxy, aroxy aralkoxy, cycloalkoxy and alkeneoxy, including methoxy, ethoxy, n-butoxy, t-butoxy, ethoxyethoxy, phenoxy, benzyloxy, diphenylmethoxy, triphenylmethoxy, cyclopropoxy, 3 diethylaminopropoxy, p dimethylaminoethoxy, phenethoxy, allyloxy, iso-propoxy, ,B-N-morpholinoethoxy, cyclopropylmethoxy, and tetrahydrofurfuryloxy; amino, secondary and tertiary amino, such as 3,466,372 Patented Sept.
• R is alkyl, substituted alkyl such as hydroxyalkyl, polyhydroxyalkyl, dialkylamino alkyl, dialkylamido, carboxyalkyl, cycloalkyl, aryl such as phenyl, alkoxyphenyl, halophenyl, aralkyl such as benzyl, cycloalkyl such as cyclohexyl, and R" may be hydrogen or any of the same radicals as R and additionally, R and R" together may be a hetero-ring such as piperidine, piperazine, morpholine, pyrrolidine and the like.
• the group may also be part of an amino sugar such as D-glucosamine, D-galactosamine, other hexylamines and pentosamines, theor O-acylated derivatives and glycosides; and OY, where Y is a cation, or
• esters, salts, anhydrides and the amides of such acid also represent simple derivatives of the acid compound which may be utilized herein.
• the esters may be obtained by treating the acid with the appropriate alcohol.
• the preferred esters are the lower alkyl esters, such as the methyl, ethyl, propyl or t-butyl compounds, and the aralkyl esters, such as benzyl, p-halobenzyl and like esters, and the aminoalkyl esters, such as 8-diethylaminoethyl, fl-piperidinoethyl, fi-diethylaminopropyl, and a-piperidinopropyl compounds.
• the salts can be obtained by treatment of the free acid with base under mild conditions.
• alkaline metal salts such as the sodium and potassium, the aluminum or magnesium salts, or saltslof alkaline earth metals, examples of which are barium and calcium.
• the amides may be obtained conveniently by treating the acid chloride of the free acid with ammonia or an alkylamine (to form an N-alkylamide).
• amines which can be used to form the amides of this invention are alkylamines, such as methylamine, ethylamine, propylamine, butylamine and the like, and dialkylamines such as dimethylamine, diethylamine, methylethylamine, methylbutylamine, dibutylamine and the like.
• dialkylamines such as dimethylamine, diethylamine, methylethylamine, methylbutylamine, dibutylamine and the like.
• hydroxylated alkylamine such as ethanolamine, diethanolamine, glucosamine, glucosylamine and the like.
• Among the more complex amines are morpholine, N-methyl-piperazine, piperazine, N-phenylpiperazine, piperidine, benzylamine, aniline, p-ethoxyaniline, cyclohexylamine, pyrrolidine, N-hydroxyethylpiperazine, carbobenzyloxymethylamine and the like.
• the anhydride may be obtained by treating the acid with dicyclohexylcarbodiamide reagent.
• the treatment of inflammation in accordance with the method of the present invention is accomplished by administering the 4-pheny'l-a-methyl-phenylacetic acid or derivative thereof in a pharmaceutically acceptable carrier, preferably in tablet or capsule form.
• a pharmaceutically acceptable carrier preferably in tablet or capsule form.
• the optimum dosage will depend upon the type and severity of the inflammation being treated, and the derivative form of the compound employed.
• the dose level of course will depend also upon the reaction sensitivity of the patient.
• Preferred oral dose levels are in the range l2000 mg. per day, suitably with 10-500 mg. per day,
• the active compound of course being present in combination with the pharmaceutically acceptable carrier material may be, for example, either a solid or a liquid.
• exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
• Exemplary of liquid carriers are peanut oil, olive oil, sesame oil and water.
• the carrier of diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• the preparation can be tableted or placed in a hard gelatin capsule.
• the amount of Solid carrier Will vary widely but preferably will be from about 25 mg. to about 1 gm.
• the preparation may be in the form of a soft gelatin capsule, placed in an ampule or in a liquid suspension Since the 4-phenyl-a-methyl-phenylacetic acid compound of the invention possesses an asymmetric carbon atom, it is ordinarily present in the form of a racemic mixture. The resolution of such racemates can be carried out by a vast number of known methods.
• racemic mixtures can be precipitated as eutectics instead of mixed crystals and can thus be quickly separated and in such cases can sometimes be selectively precipitated.
• the more common method of chemical resolution is, however, greatly preferred.
• diastereomers are formed from the racemic mixture by reaction with an opticallyactive resolving agent.
• an optically-active base can be reacted with the carboxyl group.
• the difference in solubility between the diastereomers formed permits the selective crystallization of one form and regeneration of the optically-active acid from the mixture.
• a third method of resolving which shows great promise. This is one or the other forms of biochemical procedures using selective enzymatic reaction.
• racemic acid can be subjected to an asymmetric oxidase or decarboxylase which will, by oxidation or decarboxylation, destroy one form, leaving the other form unchanged. Even more attractive is the use of a hydrolysate on a derivative of the racemic mixture to form preferentially one form of the acid.
• esters or amides of the acids can be subjected to an esterase which will selectively saponify one enantiomorph and leave the other unchanged.
• the desired ((1) isomer of the free acid may be prepared by any one of the preceding described resolving methods, preferably working from the free acid as the starting material.
• amide or salt diastereomers of the free acid may be formed with optically-active amines, such as quinine, brucine, cinchonidine, cinchonine, hydroxyhydrindamine, methylamine, morphine, a-phenylethylamine, phenyloxynaphthyl-methylamine, quinidine, l-fenchylamine, strychnine, basic amino acids such as lysine, arginine, amino acid esters, and the like.
• ester diastereomers of the free acid may be formed with optically-active alcohols, such as borneol, menthol, 2-octanol and the like.
• active a-phenylethylamine, strychnine or quinine to give readily decomposable diastereomer salts which can be fractionally crystallized to separate the two enantiomorphs.
• Example 1.4-phenyl-u-methyl-phenylacetic acid A Ethyl-biphenyl-glyoxalate. One hundred and eighty-two grams (1.18 moles) of biphenyl and 175 g. of ethyl oxalyl chloride (1.28 moles) is dissolved in 750 cc. of dry carbon disulfide and the solution poured into a 3- liter, 3-necked, round-bottomed flask equipped with a mercury-sealed stirrer and a reflux condenser; a long calcium chloride tube is attached to the latter. One neck of the flask is connected with a 500 cc. Erlenmeyer flask by means of a piece of wide rubber tubing about 8 inches long. The Erlenmeyer flask is supported by a ring stand, neck down, and 173 g. (1.30 moles) of aluminum chloride,
• a solution of methyl magnesium iodide is prepared from 4.62 g. of methyl iodide, 0.790 g. of magnesium, and 50 cc. of ether.
• a solution of 8.27 g. of ethyl-4-biphenylglyoxalate in 200 cc. of ether is cooled with an ice-salt mixture and stirred while the solution of the Grignard reagent is added to it dropwise. A yellow complex precipitates immediately. After all the ester has been added, the mixture is kept cold for one hour and then refluxed for three hours. The mixture is poured into dilute sulfuric acid, the ether layer separated and then Washed with water.
• Example 2.'y-Diethylaminopropyl-4-phenyl-u-methylphenylacetate hydrochloride A mixture of 3.39 g. of 4-phenyl-a-methyl-phenylacetic acid, in 2.05 g. of diethylaminopropyl hloride and 75 cc. of dry isopropyl alcohol is refluxed for 12 hours, the solvent removed under reduced pressure, the residue washed with dry ether and recrystallized from a mixture of dry ether and absolute alcohol; M.P. 1121l4 C.
• the y-piperidinopropyl ester is prepared; M.P. 142l44 C.; and the fi-piperidinoethyl ester; M.P. 162-164 C.
• Example 3 8-Diethylaminoethyl-4-phenyl-ot-methylphenylacetate hydrochloride
• 4-phenyl-a-methyl-phenylacetic acid and 8 cc. of thionyl chloride is refluxed for one hour and the excess thionyl chloride removed under reduced pressure; 40 cc. of dry benzene was added, the benzene distilled and the process repeated several times in order to remove all traces of thionyl chloride.
• the acid chloride crystallizes when cooled and melts at 99l0l after recrystallization from petroleum ether (90100).
• the mixture is refluxed for one-half hour on a steam bath, cooled and the precipitated fl-diethylaminoethyl alcohol hydrochloride is removed by filtration; after it has been Washed with benzene and ether it weighs 1.3 g. and melts at 133135.
• Example 4.-Ethyl-4-phenyl-u-methyl-phenylacetate A solution of 0.05 mole of 4-phenyl-a-methyl-phenyl acetic acid and 0.05 mole of ethyl alcohol in 200 ml. tetrahydrofuran containing 0.1 mole of hydrogen chloride is refluxed for 5 hours and the desired ethyl ester is distilled off and purified.
• Example 5 sodium salt of 4-phenyl-a-methylphenylacetic acid 0.05 mole of 4-phenyl-a-methyl-phenylacetic acid in 100 cc. of ethanol is neutralized with an equivalent amount of sodium hydroxide and the sodium salt is obtained from the mixture by evaporation of the solvent or by precipitation with a miscible organic solvent such as ether. The above procedure is followed to produce the barium, calcium and aluminum salts.
• Example 6.-4-phenyl-a-methyl-phenylacetarnide To a solution of 0.05 mole of the acid chloride of 4- phenyl-a-methyl-phenylacetic acid as prepared above in Example 3A in 50 ml. of 1,2-dimethoxyethane with icecooling is added 0.1 mole of ammonia. The mixture is stirred at 0 C. for one-half hour, poured into water and extracted with ether, dried over sodium sulfate and the product purified by crystallization.
• Example'8 (tablets) Ingredients: Amount, mg. 4-phenyl-a-methyl-phenylacetic acid Lactose 200 Magnesium Stearate 2.5
• One tablet is administered orally three times a day.
• Example 9 oral suspension
• Example 10 injectable
• Example 14 Ingredients 4-phenyl-a-methyl-phenylacetic acid mg 200 Freon 22 propellant (percent solution) 1
• Example l5.Resolution of 4-phenyl-ot-methylphenylacetic acid A mixture of 0.1 mole of 4-phenyl-a-methyl-phenylacetic acid and 0.1 mole of l-a-phenethylamine is dissolved in 500 ml. of a hot 4:1 benzene-ethanol mixture. On cooling, the resulting salt is filtered off. This is then fractionally crystallized from a benzene-ethanol mixture to constant optical activity.
• the free acid is obtained from the purified salt by acidification with dilute hydrochloric acid.
• the diastereomeric salt is recovered from the original mother liquor by concentration in vacuo. It is again fractionally crystallized from benzene-ethanol to constant optical activity and acidified to give the enantiomorphic free acid.
• a method of treating inflammation which comprises administering to a patient suflering from inflammation between 12,000 mg. per day of dl-4-phenyl-amethyl-phenyl acetic acid to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of a compound having the formula:
• M is lower alkoxy to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient sufiering from inflammation between 12,000 mg. per day of a compound having the formula:
• Y is an alkaline earth metal, an alkali metal, aluminum or magnesium to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suflering from inflammation between 12,000 mg. per day of dimethylaminoethyl-4- phenyl-a-methyl-phenyl acetate to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of benzyl-4-phenyla-methyl-phenyl acetate to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suflFering from inflammation between 12,000 mg. per day of diethylaminoethyl-4- phenyl-a-methyl-phenyl acetate to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of 4-phenyl-tx-methyl-phenyl acetamide to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of 4-phenyl-a-methyl-phenyl acetmorpholide to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of ethoxy ethyl-4- phenyl-u-methyl-phenyl acetate to produce thereby a reduction of the degree of inflammation of said patient.
• a method of treating inflammation which comprises administering to a patient suffering from inflammation between 12,000 mg. per day of 4-phenyl-a-methyl-phenyl acet-D-glucosamide to produce thereby a reduction of the degree of inflammation of said patient.

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Cited By (7)

• 1965
  • 1965-05-06 FR FR16112A patent/FR4841M/fr not_active Expired
• 1967
  • 1967-04-14 US US647302A patent/US3466372A/en not_active Expired - Lifetime

Non-Patent Citations (1)

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